SUMMARY ? PATHOLOGY CORE The Pathology Core (PC) will assemble and characterize the reagents critical for this proposal including the wide array of engineered mouse models, clinically and molecularly annotated primary samples, patient derived tumor xenograft (PDTX) models as well as patient derived organoids (PDOs). These resources will be provided to project leaders to cross validate experimental findings, define the pathogenetic role of defined lesions and identify their relevance in human tissue samples using PDTX and PDO models. We anticipate that the services of the PC core will provide the basis for the biological dissection of the genetic lesions described in all three Projects, leading to a deeper knowledge of how 3D genome organization plays a crucial role in gene regulation, oncogenic transcriptional programs and the design of more efficient therapeutic approaches. Translational cancer research has been greatly facilitated by the demonstration that defined genomic defects are associated with unique functional fingerprints which can be effectively validated in vitro using primary 2D and 3D cultures and by employing innovative transgenic mouse models and tumor xenografts in immunocompromised mice. Importantly, primary 2D and 3D cultures and tumor xenografts have been tested showing that they largely mimic the original patient tumor, including tumor heterogeneity and can effectively predict response to therapies. Of note, models from primary patient derived cultures or PDTX have proven to be more informative than conventional cells lines allowing precise determinations and more reliable assessments. Lastly, as many as 85% of drugs with in vitro activity in established cell lines have failed in human studies, primarily because of a lack of efficacy in complex systems or in human settings. Thus, our models are particularly useful for in vivo mechanistic studies (Projects 1-3), and the information they provide will be instrumental in understanding the pathogenic potential of the defects investigated in this application, leading to potential targeted therapies (Projects 2 and 3).